Streptococcus pneumoniae is a rather ubiquitous human pathogen, which can infect several organs including lungs, the central nervous system (CNS), the middle ear, and the nasal tract. Infection of these tissues results in various symptoms such as bronchitis, pneumonia, meningitis, and sinus infection. S. pneumoniae is a major cause of bacterial meningitis in humans and is associated with significant mortality and morbidity despite antibiotic treatment. Quagliarello et al., (1992) N. Eng. J. Med. 327: 869-872. S. pneumoniae meningitis can cause persistent neurological sequelae. The incidence of S. pneumoniae meningitis in developed versus developing countries are 1-2 and 20 per 100,000 population, respectively. Anon, (2000) CDSC European Bacterial Meningitis Surveillance Project. The fatality rate of pneumococcal meningitis in the USA is approximately 18%. Fedson et al., (1994) Arch. Intern. Med. 154:2531-2535. The highest incidence of pneumococcal meningitis occurs in children between 1-4 years of age (30% of all bacterial meningitis), followed by 15-19 year olds (14%) and 1-11 month old infants (13%). Anon, (2000) CDSC European Bacterial Meningitis Surveillance Project. The elderly are also seriously affected by streptococcal meningitis in both developed and developing countries. Butler et al., (1999) Drugs Aging 15 (Suppl. 1): 11-19; Fedson et al., (1999) Vaccine 17 Suppl. 1: S11-18.
The major reservoir of pneumococci in the world resides in human nasal carriage. Acquisition of infection is generally from a carrier and infection is always preceded by nasal carriage. The colonization of the nasopharynx is considered a prerequisite for the spread of pneumococci to the lower respiratory tract, the nasal sinuses, and the middle ear. Thus, any medical intervention that prevented carriage would not only eliminate the risk of disease in the treated individuals but would also result in herd immunity and greatly lower the risk of infection even in untreated members of the community. Although S. pneumoniae is an important human pathogen, relative little is known about the mechanisms by which S. pneumoniae causes either nasal carriage or meningitis.
Some data exist to suggest that neuraminidases are unique virulence factors for the nasal tract. One such observation comes from the study of the NanA-deficient, S. pneumoniae strain D39, which is eliminated faster from the nasopharynx than is its parent strain. Tong et al., (2002) Infect. Immun. 68: 921-924. Neuraminidase cleaves terminal sialic acid residues from a wide variety of glycolipids, glycoproteins, and oligosaccharides on the host cell surfaces and in body fluids. Elevated levels of free sialic acid in the cerebrospinal fluid (CSF) of patients with pneumococcal meningitis are associated with a poor prognosis. O'Toole et al., (1971) J. Clin. Invest. 50: 979-985. The importance of this enzyme for S. pneumoniae virulence in humans is further illustrated by the findings of two independent studies where every new clinical isolate of S. pneumoniae had neuraminidase activity. O'Toole et al., (1971) J. Clin. Invest. 50: 979-985; Kelly et al., J. Bacteriol. 94: 272-273. Moreover, mouse passage of isolates of pneumococci, which frequently increases their virulence, has been reported to also result in 2-5-fold increase of neuraminidase activity. Vishniakova et al., (1992) Zhurnal Mikrobiologii, Epidemiologii i Immunobiologii 9-10: 26-9. Pneumococcal C-polysaccharide, also known as teichoic acid, is structurally identical to the polysaccharide portion of pneumococcal F-antigen, also known as lipoteichoic acid. Fischer et al., (1993) Eur. J. Biochem 215: 851-857. These molecules are unique features of S. pneumoniae among gram-positive bacteria. The immunodominant determinants on these molecules are the phosphorylcholine (PC) residues and Abs to PC are protective against intraperitoneal, intravenous, or nasal pneumococcal challenge. Briles et al., (1984) Eur. J. Immunol. 14: 1027-1030; Briles et al., (1981) Nature 294: 88-90; Yother et al., (1982) Infect. Immun. 36: 184-188; Briles et al., (1984) J. Mol. Cell. Immunol. 1:305-309. However, as all of these studies assessed protection against systemic infection medicated by serum, no information is available regarding the ability of these Abs to protect against nasal colonization. Surface phosphocholine residues are, however, common on the surface of respiratory bacteria. Lysenko, et al., (2000) Infect. Immun. 68:1664-71.
The mechanisms by which S. pneumonia causes nasal carriage and subsequent disease are relatively unknown. No studies to date have determined a mechanism by which nasal carriage is reduced or prevented. Since colonization of the nasopharynx is considered a prerequisite for the spread of pneumnococci to the lower respiratory tract, the nasal sinus, systemically, and to the brain, what is needed in the art is a means of providing mucosal immunity at the site of initial pneumococcal colonization. Preventing initial pneumococcal colonization in the nasopharynx, will prevent nasal carriage and reduce spread of S. pneumoniae between individuals. Moreover, providing immunity at the mucosal surfaces of the nasopharynx would prevent or reduce subsequent disease caused by S. pneumoniae. 